She was only 12, but she remembers the last time she saw her grandfather in the hospital. He was a great storyteller and always had wonderful bedtime stories, but those had stopped a while ago. Now she could see he had so much to say, but couldn’t speak. He could barely breathe. He mouthed the words “I love you”, and Stacy said “I love you too”. He had been so brave and never complained. She tried not to let him know she had been crying. What Stacy was too young to realise was that her grandfather was dying of ALS.

Looking back today, Stacy sees that, beyond the physical pain of this horrendous disease, she couldn’t imagine the kind of mental turmoil her grandfather faced. His mind was as sharp as ever, but he was trapped in a crumbling and unresponsive body. Stacy once overhead him say to her mother that he felt like he had been buried alive. But he never showed it, and just seemed grateful for every precious moment. She knew he had taught her more about life by dying than anyone ever had, and she would never forget him or the horror of ALS.

A diagnosis of ALS (amyotrophic lateral sclerosis, better known as Lou Gehrig’s disease in the US) or Alzheimer’s disease (AD), leaves patients with little hope. Even today, there are no approved treatments that can prevent, slow or reverse these devastating, progressive conditions. However, thanks to Aquinnah Pharmaceuticals, an innovative lab in Cambridge, Massachusetts, there is real hope at last. Aquinnah has developed a completely new approach to ALS (as well as AD and other neurodegenerative diseases) that has the potential to arrest, and possibly even reverse, the effects of these conditions.

Looming epidemic
As the population ages, the incidence of neurodegenerative disease in the US alone will rise dramatically. For the first time in human history, there will be more people in the world over the age of 65 than under the age of five, according to the US National Institute of Aging. They will represent 16 percent of the world’s population. To put this in context, in 1950 they only represented five percent. This will have a profound effect on society and overall quality of life during old age.

Without any breakthroughs in treatment, it’s estimated the number of people with Alzheimer’s disease will nearly triple by 2050. The number of people with Parkinson’s will likely more than double from its 2005 level by 2025. According to a recent study in Nature Communications, ALS is also predicted to increase at a startling rate in the US – a 70 percent increase by 2040. Taken as a whole, this runaway growth will strain both family and healthcare systems, drive costs up significantly and, most tragically, increase human suffering.

Twin threats – ALS and AD
ALS is a progressive fatal disease, caused by the loss of motor neurons in the brain. These neurons control muscle movement and eventually shut down one’s ability to walk, talk, swallow and, finally, breathe. ALS progresses rapidly, killing over half of patients within three years of diagnosis. The only drug available, approved almost two decades ago, extends survival by just two to three months.

AD causes a gradual loss of memory and executive function, i.e. the ability to perform complex reasoning and decision making. Few other diseases create such fear; fear of getting it, fear of losing your identity and connection to loved ones, and fear of losing control of your life. Unsurprisingly, AD places significant pressure on both family structure and financial resources. The condition strikes one out of every 10 people aged over 65, with about 5.4 million individuals suffering from AD in the US alone at any given time. Despite a general decrease in fatalities for other major diseases over the last decade, Alzheimer’s deaths increased an incredible 71 percent, according to the Alzheimer’s Association.

The discovery
The discovery of the connection between stress granules – aggregations of protein in the brain – and neurodegenerative disease has opened up the possibility that ALS, AD and other neurodegenerative diseases can be arrested and potentially reversed.

Aquinnah’s innovative approach is one of the most promising discoveries today, and could offer amazing new hope for those suffering from neurodegenerative diseases. Stress granules are the body’s way of repairing itself. For example, if you hit your head, your body immediately goes into repair mode and creates stress granules to make the repairs. Normally, when the damage is repaired, the stress granules disperse. This is a process that usually takes 10-15 minutes. But, if you have a mutation that makes them ‘stickier’, the stress granules build up and become persistent. This is the pathology that’s found in most neurodegenerative diseases. The location of the persistent stress granules determines the symptoms. Accumulation in the spinal cord results in motor dysfunction and ALS, while accumulation in the hippocampus of the brain causes memory loss and AD.

Aquinnah has discovered several compounds that measure up against the most exacting standards: they are potent, orally bio-available in small doses, and can get past the blood brain barrier

Dr Ben Wolozin is co-founder and Chief Scientific Officer of Aquinnah and Professor of Pharmacology and Neurology at Boston University School of Medicine. His lab was the first to show that the aggregates in ALS and AD are persistent stress granules. Like many great discoveries, this took place by accident. Wolozin happened to run into a colleague who was studying stress granules, unrelated to the brain. At the time, Wolozin wasn’t particularly interested, but the discovery of TDP-43, a key protein in stress granules in ALS patients by Drs Lee and Trojanowski, two of the most important researchers in the study of neurodegenerative disease, changed his mind.

The next step was for Wolozin to insert a gene for TDP-43 carrying a florescent marker into neuronal cells. Then, he and his team stressed the cells and discovered something they had never seen before. Wolozin wasn’t quite sure what it was, but he thought: “If I were a stress granule, I would probably look something like that.” And he was right – it was a stress granule.

After learning how these proteins, the building blocks of stress granules, worked, he realised they existed on the verge of aggregation, and were ready to go haywire if the body’s physiology shifted just a bit. That was the lightbulb moment. Wolozin knew chemical modifications control whether the stress granule proteins stick together, and hypothesised that if he could inhibit this process, he could prevent or reverse the accumulation of stress granules.

The breakthrough
The team tested over 75,000 different compounds and identified a small number that could eliminate stress granules. This discovery has the potential to change the course of neurodegenerative disease and give patients something close to their old lives back. While there is agreement among the scientific community that stress granule proteins are the cause of more than 90 percent of ALS cases and an estimated 50 percent of AD cases, Aquinnah is the only company doing drug discovery and development to eliminate persistent stress granules. This potential breakthrough is especially significant after years of disappointment in ALS and Alzheimer’s research.

Before the discovery of TDP-43 stress granules, researchers spent 20 years studying SOD1, the first gene discovered that caused ALS. The problem was SOD1 only occurs in two percent of patients with ALS. Despite many attempts, none of the trials targeting SOD1 was successful in finding an effective therapy for ALS.

For AD, the field has been focused on trying to break up the plaques that are thought to have a causal role. According to Wolozin: “Until now, we have only known the fact that plaques and tangles accumulate; we haven’t known how or why, or why they are bad. For the first time, the stress granule provides a manual for understanding the biology of how tangles form. With that, we can troubleshoot problems. We have a work plan for how to reverse-engineer the system.”

Experienced team
Dr Glenn Larsen, co-founder and CEO of Aquinnah, has assembled an elite team of award-winning scientists to take on the challenge of ALS and AD. His passion for finding a cure is born out of his commitment to help patients overcome these deadly diseases, and his belief that Aquinnah is on the verge of a major breakthrough.

Larsen has been a drug hunter all his life. He has a strong track record and has helped bring 15 drugs to clinical development and five drugs to market, with sales of over $10bn. He knows the ingredients for creating a successful drug because he has experience at major pharmaceutical companies in all facets of drug discovery and development. Larsen also brings a unique skillset to his role as CEO. With a PhD in biochemistry and a PMD from Harvard, he is well acquainted with the worlds of science and business, and understands how to marry the two. He brings a rare combination of basic science, pharmaceutical drug discovery and development, and clinical trial, regulatory, patent and business development experience.

Wolozin holds MD and PhD degrees, and has extensive research experience in this field. Despite tremendous advances in our understanding of the brain, he has been frustrated that so little can currently be done for patients. Wolozin identified one of the first molecular markers for the tangle pathology that accumulates in neurons in AD, and was the first to identify the link between the use of statins (a cholesterol-lowering drug) and reduced rates of AD. He has won multiple awards for his research, including the prestigious Zenith Fellows Award and the AE Bennett Award from the Society
for Neuroscience.

Like Larsen, Wolozin sees genetics as key to their success. Because mutations in stress granules cause ALS, Wolozin is confident they can develop a drug to target this gene: “Genetics is nature’s way of telling you what’s wrong. When you understand the machine, you can begin to repair it.”

Parameters of success
Aquinnah has discovered several compounds that measure up against the most exacting standards: they are potent, orally bio-available in small doses, and can get past the blood brain barrier – a critical factor that hasn’t always been tested by others in the field. Aquinnah has been awarded four peer-reviewed grants – two from the ALS Association, and one each from the National Institute of Health and the Massachusetts Life Science Center – in the past year. The firm’s approach has also garnered support and interest from major pharmaceutical companies, including Takeda Pharmaceuticals.

Aquinnah is the leader in this innovative new drug therapy for ALS and AD. The company is currently conducting animal trials, with human trials scheduled to begin in the next two to three years. Once in human trials, they should know in one year if the drug is effective, because ALS is such a rapidly progressing disease. Once the drug is proven successful in ALS patients, they will begin AD trials.

Before the discovery of TDP-43 stress granules, researchers spent 20 years studying SOD1, the first gene discovered that caused ALS. The problem was SOD1 only occurs in two percent of patients with ALS

Both Larsen and Wolozin are very optimistic about the future of neurodegenerative disease. The discovery that the molecules in stress granules are the building blocks of neurodegenerative disease provides a new foundation for not just one, but potentially many new therapies.

Larsen explained: “We like to think we’ve eliminated much of the risk that’s typically been associated with investing in a neurodegenerative drug development programme. We have a proven human genetic cause, validated human pathology of the same gene present in over 90 percent of ALS patients, initial proof-of-concept for drug candidates, and a highly experienced team of drug developers.”

Historically, of all branches of medicine, neurology has the most unknowns and the fewest treatments. However, Wolozin believes that is about to change: “Scientists have been studying the molecular mechanisms of these diseases for 30 years. We have to remember that progress moves in increments. It took a long time to go from the invention of the telephone to the iPhone. Drug development also takes time, but can make similar dramatic leaps forward. I believe neuroscience is on the cusp of a breakthrough. We are about to enter a golden age for neurodegenerative disease.”